The increasing prevalence of sexually transmitted diseases (STDs) is a serious public health problem affecting both developing resource-constrained countries. In the latter, the acquired immunodeficiency syndrome (AIDS) epidemic is taking a devastating toll in human lives. According to the World Health Organization, almost 40 million people were living with HIV at the end of 2006, a year in which 4.3 million people were newly infected and 2.9 million died of AIDS-related diseases. Most new infections are occurring in the developing world, where women are most vulnerable. In sub-Saharan Africa, for example, 57% of people living with HIV are women, and young women between 15 and 24 years old are at least three times more likely to be HIV positive than young men.
There are no candidate vaccines in the pipeline that can induce sterilizing immunity and protect against infection with HIV. Therefore, there is an urgent need to develop additional safe and effective preventative strategies. One of those strategies has become known as microbicides, topically applied agents that prevent or reduce transmission of infectious disease, in particular HIV/AIDS (Lederman, M. M and Offord, R. E, Hartley, O. Nat Rev Immunol. 2006. 6: 371-382).
According to their mechanism of action, the microbicide pipeline contains virucides (i.e., compounds that directly inactivate or destroy the virus), entry inhibitors, replication inhibitors, and integration and post-integration inhibitors (Doncel, G. and Mauck, C. Curr HIV/AIDS Rep. 2004. 1: 25-32). Within the replication or reverse transcriptase inhibitors (RTIs), there are only a few, namely, UC-781 (Thiocarboxanilide), TMC-120 (Dapivirine) and MIV-150 (N-(5-cyano-2-pyridinyl)-N′-[1S,2S)-2-[6-fluoro-2-hydroxy-3-(1-oxopropyl)phenyl]cyclopropyl]urea) all non-nucleoside RTIs, and PMPA (Tenofovir), a nucleotide analogue. Although they are the most potent microbicides in development, these agents, especially the non-nucleosides, have poor water solubility and high susceptibility to induce resistant virus. In part, this is due to the fact that they act through a very specific, but single mechanism of action. They are also less effective against cell-associated virus.
Another factor that compounds the problem of fighting the epidemic is the continued development of drug-resistant virus. New and more potent anti-HIV agents are constantly needed as existing therapies succumb to newly developed resistant virus.